11-oxygenated 16 alpha-hydroxy-4-androstene-3, 17-diones and process



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II-OXYGENATED 16a-HYDROXY-4-ANDRO- STENE-3,17-DIONES AND PROCESS ArthurR. Hanze, John A. Hogg, and Alan H. Nathan, all of Kalamazoo Township,Kalamazoo County, Mich, assignors to The Upjohn Company, Kalamazoo,Mich, a corporation of Delaware No Drawing. Filed May 4, 1959, Ser. No.810,579

6 Claims. (Cl. 260-39745) The present invention relates .toll-oxygenated 16ozhydroxy-4-androstene-3,17-diones, i.e.,1lfi,l6a-dihydroxy-4-androstene-3,l7-dione andl6ahydroxy-4-androstene-3,11,i7-trione, and to the process for theproduction thereof.

The compounds and process of the present invention are represented bythe following formulae:

wherein X is selected from the group consisting of thefl-hydroxymethylene radical and the corbonyl radical, and R is the acylradical of an organic carboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive.

The novel compounds of the present invention possess central nervoussystem depressant activity manifested by sedative and hypnotic activity.These compounds are useful in the treatment of neurosis as manifested byhypertension, anxiety, etc., in psychotic conditions wheretranquilization is desirable and in related disorders.

The compounds of this invention can be prepared and administered to theanimal organism in a wide variety of oral and parenteral dosage forms,singly, or in admixture with other coacting compounds. They can beassociated with a carrier which can be a solid material or a liquid inwhich the compound is dissolved, dispersed or suspended. The solidcompositions can take the form of tablets, powders, capsules, pills, orthe like, preferably in unit dosage forms for simple administration orprecise dosages. The liquid compositions can take the form of solutions,emulsions, suspensions, syrups, or elixirs.

The process of the present invention comprises: ozonolyzing (i.e.,treating with ozone at low temperature to obtain an ozonide anddecomposing the ozonide thus produced, usually by zinc and acetic acid)and 11- oxygenated 16a-hydroxy 2.1- acyloxy-4,17 (20)-pregn-adien-3-oneto produce the corresponding ll-oxygenatedl6a-hydroxy-4-androstene-3,17-dione.

Starting materials for the process of the present invention arel1,8,16a-dihydroxy-21-acyloxy-4,17(20)-pregnadien-3-one and16a-hydroxy-21-acyloxy-4,17(20)-preg nadien-3,11-dione in which the acylradical is that of an organic oarboxylic acid, preferably a hydrocarboncarboxylic acid containing from one to twelve carbon atoms, inclusive,produced as shown in Preparations 1 rates Patent Z and 2, theZI-acetates being the preferred starting materials.

According to process of the present invention, ozone is passed into asolution of an ll-oxygenated 16a-hydroxy- 21acyloxy-4,17(20)-pregnadien-3-one at :a temperature below approximatelythirty degrees centigrade, preferably between approximately minus thirtyand approximately minus eighty degrees centigrade, to produce thecorresponding ll-oxygenated 16a-hydroxy 2l-acyloxy-4,l7 (20)-pregnadien-3-one 17 ,20-ozonide.

Representative solvents which can be used for the ozoniz-ation include,chloroform, ether, methylene chloride, ethyl acetate, mixtures of thesesolvents, and the like. The addition of a small amount of pyridine issometimes advantageous in improving the yield of the 17,20-oxonide. Thepreferred solvent is chloroform in the presence of a small amount ofpyridine.

The 17,20-ozonide, thus obtained, is decomposed by any of the usualdecomposition procedures, for example, by reductive decomposition withzinc and a lower organic acid, i.e., formic, acetic, propionic, etc.; bysteam distillation; by the addition of an aqueous solution of .potassiumor sodium bisulfite; and the like, to give the correspondingll-oxygenated 16z-hydroxy-4-androstene- 3,17-di0ne. Reductivedecomposition with zinc and acetic acid is preferred.

The thus obtained ll-oxygenated 16a-hydroxy-4-androstene-3,l7-dione isrecovered by conventional methods, such as removal of the zinc byfiltration and concentration of the reaction mixture by evaporation. Thecrude 17-keto steroid is then purified by conventional methods such asby chromatography and recrystallization from a suitable solvent, suchas, ether, methanol, ethanol, acetone, Skellysolve B hexanes, benzene,ethyl acetate, and the like. Ethyl acetate is the preferred solvent.

The following preparations and examples are illustrative of the processand products of the present invention, but are not to be construed aslimiting.

PREPARATION 1Jfl,I6u-dihydr0xy 21 acetoxy-4,17(20)-pregnadien-3- one Amixture of 3.7 g. of 1lB-hydroxy-21-acetoxy4,l7 (20)-pregnadien-3-oneand 1.10 g. of selenium dioxide in 55 ml. of dioxane and 15 ml. of waterwas heated under reflux for one hour. The solution was filtered toremove the selenium. The filtrate was diluted with water and extractedwith methylene chloride. The methylene chloride extractions werecombined and concentrated by distillation giving 4.54 g. of a yellowoil. The oil, thusobtained, was dissolved in ethyl acetate andcrystallized, yielding 2 g. of 11,8,16u-dihydroxy-2l-acetoxy-4,17(20)-pregnadien-3-one melting at 172 to 177 C. An analytical samplewas prepared by chromatography over alumina (aluminum oxide) followed byrecrystallization from ethyl acetate. The analytical sample melted at179.5 to 181 C.

Analysis. -Calc. for C H O C, 71.10; H, 8.30. Found: C, 71.10; H, 8.14.

In the same manner as described above and substituting other 21-acylatesof 1lfl,2l-dihydroxy-4,l7(20)pregnadien-3-one in place ofl1fi-hydroxy-21-acetoxy-4,17(20)- pregnadien-3-one, the abovepreparation is productive of other 21-acylates of1lfi,l6a,21-trihydroxy-4,l7(20)-pregnadien-3-one, such as, for example,

1 113, l6a-dihydroxy-21-propionyloxy-4, 17 (20) -pregnadien- 115,16dihydroxy 21 butyryloxy 4,17 (20) pregnadien-3-one,

and the mixture was stirred for 20 minutes.

'Was washed with water six times.

tion was dried over'sodium sulfate.

115,16 dihydroxy 21 hexanoyloxy 4,17(20) pregnadien-S-one,

1119,16 dihydroxy 21 trimethylacetoxy 4,17 (20)- I pregnadieneig-one,

11 ,160. dihydroxy 21 isovaleryloxy 4,17 1 2o 115,160: dihydroxy 21acrylyoxy 4,17(20) pregnadien-3 one,

115,160 dihydroxy 21 undecolyloxy 4,17 20 pregnadien 3 one, 11 3,16dihydroxy 21 maleyloxy 4,17(20) pregnalien-S-One, 1113,16oc-dihYdl'0XY21 salicyloyloxy 4,17(2 0) pregnadien-3-one,

11 3,1601 dihydroxy 7 21 chloroacetoxy 4,17(20)- pregnadien -3-one,115,160: dihydroxy 21 benzenesulfonyloxy 4,17(20)- pregnadien-B-one, andthe like.

PREPARATION 2 i 1 6a-hydr0icy-21-acet0xy-4J 7 (20)-pregnadiene- 3,11dione A mixture of 14.5 g. of 21-acetoxy-4,17(20)pregnadiene-3,11-dione,215 ml. of dioxane, 50 ml. of water and 4 g. of selenium dioxide washeated under reflux for one hour. After cooling the reaction mixture to26 C., 5.5 g. of Magnesol (synthetic magnesium silicate) was added Thesolids were removed by filtration and the filtrate was diluted with 1 l.of methylene dichloride. The organic solution Raney nickel, previouslywashed with methyl alcohol, wasadded to the solution and the mixturewasstirred for 20 minutes. After filtering through Filter-Coldiatomaceous earth, the solu- The solution was then concentrated todryness and the crude product was recrystallized from ethyl acetate togive crystals of 16ahydroxy 21 acetoxy 4,17(20)-pregnadiene-3,1l-dionemelting at 233 to 236 C. and weighing 6.9 g. An analytical sample wasprepared by recrystallization from ethyl acetate to give16u-hydroxy-21-acetoxy-4,17(20)- pregnadiene3,11-dione melting at 245 to246 C., [al 145 (chloroform).

Analysis.Calc. for C H O C, 71.48; H, 7.82. Found: C, 71.23; H, 7.53.

In the same manner as described above and substituting as startingmaterial other 21acylates of 21-hydroxy- 4,17(20)-pregnadiene-3,1l-dionein place of 21-acetoxy- 4,17(20)-pregnadiene-3,1l-dione, the abovepreparation is productive of other 2l-acylates of 16a,21-dihydroxy-4,17(20)-pregnadiene-3,1l-dione, such as, those 21-acylates listed inPreparation 1, for the corresponding 11;?- hydroxy compounds, forexample, 16a-hydroxy-21-propionyloxy-4, 1 7 (20) -pregnadiene-3,1l-dione, 16a-hydroxy- 21-butyryloxy-4,17(20)-pregnadiene-3,11-dione, andthe like.

EXAMPLE 1 1113,] 6 ot-dihydroxy4-androstene-3J 7-di0ne A solution of0.513 g. of 11 p3,16ot-dihydroxy-21-acetoxy- 4,17 (20)-pregnadien-3-onein 25 ml. of methylene chloride and 0.5 ml. of pyridine was cooled in aDry Iceacetone bath. Ozone was passed into the solution at apredetermined rate such that in 6.5 minutes equiva- 4 lents had passedthrough the solution producing the ozonide of 116,160; dihydroxy 21acetoxy 4,17(20)- pregnadien-3-one. By collection of the'exit gases in atrap of aqueous potassium iodide and titration of the iodine liberatedtherein, 0.5 equivalent of ozone was found to have passed throughunused, making a net absorption of 1.06 equivalents. Ten milliliters ofacetic acid and 0.05 g. of zinc dust were added to the ozonide solutionthus produced, and the mixture was stirred for one hour at a temperatureranging'from zero to five degrees Centigrade and for another hour atabout 25 degrees centigrade to decompose the ozonide. The zinc wasremoved by filtration and the methylene chloride filtrate was washedwith' water, aqueous 'sodium' bicarbonate solution and dried overmagnesium sulfate. The solvent Was evaporated, giving 0.434 g. of crude1119,16u-dihydroxy 4 androstene 3,17-dione. The 11,3,160c-dil1Y-droxy-4-androstene-3,l7-dione thus produced was chromatographed on 43.0g. of synthetic magnesium silicate and eluted with -ml. fractions asfollows:

TABLE I Fractions Solvents methylene chloride. 6 percent acetone inSkellysolve B hexanes. 10 percent acetone in Skellysolve B hexanes. 20percent acetone in Skellysolve B hexanes.

Fractions 9 to 16 were combined and evaporated to dryness, giving 324mg. of 11p,16a-dihydroxy-4androstene-3,17-dione. A sample of the11fl,16u-dihydroxy- 4-androstene-3,17-dione thus produced wasrecrystallized from acetone-ether and then from ethyl acetate giving11B,16a-dihydroxy-4-androstene-3,17-dione melting 'at 164 to 166 C. andhaving infrared absorption maxima at 3380, 3260, 1744, 1652, and 1615reciprocal centimeters. Further recrystallization from ethylacetate'gave crystals of 11B,16 -dihydroxy-4-androstene-3,17-dionemelting at 222 to 224 C. Subsequent preparations always gave thehigher-melting material, which is the more stable polymorphic crystalform of 11 8,16a-dihydroxy4-androstene- 3,17-dione.

Analysis-Cale. for C H O C, 71.67; H, 8.23. Found: C, 71.93; H, 8.46. i

In the same manner, substituting as starting material other 21 acylatesof 16B,16a,21 trihydroxy 4,17(20)- pregnadien-S-one, which can beprepared according to the procedures disclosed in Preparations 1 and 2,in place of 1113,1601 dihydroxy 21 aeetoxy 4,17(20)-pregnadien- 3-one,the above procedure is productive of115,16a-dihydroxy-4-androstene-3,17-dione.

EXAMPLE 2 16a-hydr0xy-4-andr0stene-3,11,1 7-tri0ne A stoichiometricequivalent amount of 16a-hydroxy- 21 acetoxy-4,17(20) pregnadiene 3,11dione or other 16a-hydroxy2 1-acy1oxy-4, 17 (20) pregnadiene-3 ,1l-dione is substituted for l15,1Gu-dihydroxy-Z1-acetoxy-4,17(20)-pregnadienc-S-one in the procedure of Example 1, to obtainIGa-hYdI'OXY-4-3I1dIOSE6118-3,11,17-tli0fle, acryst-alline solid.

:It is to be understood that the invention is not to be limited to theexact details of operation or exact materials'shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is, therefore, tobe limited only by the scope9f the appended claims.

We claim: 3. 16a-hydroxy-4-androstene-3,11,17-trione.

1. An 11-oxygenated 16a-hydroxy-4-androstene-3,17- 4. The process forthe production of ll-oxygenated dione of the formula:16a-hydroxy-4-androstene-3,17-dione which comprises: CH subjecting 11oxygenated 16oz hydroxy 21 acyloxy- O 5 4,17(20)-pregnadien-3-one17,20-ozonide to reductive H decomposition to produce the correspondinglloxygen' ated 16a-hydroxy-4androstene-3,17-dione.

X 5. The process of claim 4 wherein the reductive decomposition iscarried out using zinc and a lower organic acid.

10 6. The process of claim 5 wherein the lower organic acid is aceticacid.

References Cited in the file of this patent wherein X is selected fromthe group consisting of the UNITED STATES PATENTS p-hydroxymethyleneradical and the carbonyl radical. 15 2,853,502 Thomas et a1 Sept 23,1958 2. 11B,16a-dihydroxy-4-androstene-3,17-dione. 2 857 403 Fried Oct21 1958 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Non2,951,858 September 6 196G Arthur R Hanze et all It is herebfl certifiedthat error appears in the-printed specification of the above "numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 1, line 36 for "corbonyl" read carbonyl column 2 line 16, for"oxonide" read ozonlde column 4,, line 51, for "16B l6d,2l-" read 11B166%21- (SEAL) Attest: ERNEST W. SWIDER XXNX Attesting Oflicer ARTHUR W.CROCKER A ti g Commissioner of Patents

1. AN 11-OXYGENATED 16A-HYDROXY-4-ANDROSTENE-3,17DIONE OF THE FORMULA: